Aging is a significant risk factor for developing many chronic diseases, and gaining a better understanding of the genetic, molecular, and cellular processes responsible for the aging process is vital to improving quality of life. To this end, two studies, funded in part by NIA and published in Nature, used mouse models to catalog and identify multiple cell-specific and cellular composition changes in different cell types and organs related to the aging process.
The first study describes the creation of a single-cell transcriptomic mouse cell atlas that captures cell-type-specific hallmarks across the lifespan of the mouse. The Tabula Muris Senis or Mouse Aging Cell Atlas provides molecular information on age-related changes in specific cell types across 23 tissues and organs. In the second study, using data from the atlas, researchers found that not only do cell-specific changes occur across multiple cell types and organs, but age-related changes also occur in the cellular composition of different organs.
To create the mouse atlas, researchers performed single-cell RNA sequencing on more than 350,000 cells from male and female mice ranging from one to 30 months old, which models the human aging process from infancy to approximately 100 years old. Data were collected for mice in six age groups at 1, 3, 18, 21, 24 and 30 months. By analyzing multiple organs from the same mouse over that time span, researchers were able to obtain data controlled for age, environment, and epigenetic effects.
Researchers observed that changes in the relative composition of a given cell type with age are more meaningful than comparing proportions of different cell types at a single age. In one analysis of their data, they used the Genome Analysis ToolKit to identify specific gene mutations across all samples simultaneously. They focused on genes that were expressed in at least 75% of cells for each age group within a particular tissue and observed an age-related increase in mutations across all the organs they analyzed. This supports other studies indicating that genomic instability is a hallmark of aging and suggests it occurs in many organs of the body.
In the second study, researchers performed bulk RNA sequencing of proteins and data from the mouse atlas to demonstrate a progression of aging both within and among different organs.
They measured plasma proteins and sequenced RNA from 17 isolated organ types from male and female mice from one month old to maturity (3-6 months old) and aging through adulthood (median 27 months old). Researchers then analyzed whether differentially expressed genes (DEGs) arise and whether they persist with advancing age. Differential gene expression is the activation of different genes within a cell that define its function.
Few DEGs were observed between organs at similar ages but they increased markedly with advancing mouse age, especially when compared with one-month-old mice that were undergoing development. Among their findings on DEGs, they discovered gene expression trajectories that were similar to aging-related processes, including mitochondria dysfunction, impaired protein folding, and inflammation. They also noted that changes in DEGs for common biological pathways in tissues did not seem to be driven by changes in transcription regulatory factors, which turn gene expression on and off. This suggests that additional gene regulatory sites may come into play in the dynamics of DEGs with aging. Further, researchers found that DEGs that began in middle age were highly correlated to similar patterns in later life, indicating that some harmful changes begin earlier in life. The researchers noted that better understanding of these processes may lead to improved interventions to enhance healthspan benefits.
These studies highlight the utility of the Mouse Aging Cell Atlas, as well as the work that can stem from enhanced understanding of aging processes at the cellular, tissue, and organ system level. Future research using these characterizations of aging may help with the development and application of interventions to increase the healthspan and delay aging-related diseases. The mouse atlas data set is available at https://tabula-muris-senis.ds.czbiohub.org/.
This research was supported in part by NIA grants R01-AG045034 and DP1-AG053015.
References: Tabula Muris Consortium. A single-cell transcriptomic atlas characterizes ageing tissues in the mouse. Nature. 2020;583(7817):590-595. doi: 10.1038/s41586-020-2496-1.
Schaum N, et al. Ageing hallmarks exhibit organ-specific temporal signatures. Nature. 2020;583(7817):596-602. doi: 10.1038/s41586-020-2499-y.